Tears provide nourishment to the anterior eye and are necessary for its protection from potentially damaging stimuli (Dartt et al., Frog Retin Eye Res 28: 155-177, 2009). Corneal primary afferent neurons involved in noxious stimulus-evoked tearing include both polymodal and mechanoreceptive neurons, and increased tearing caused by activation of these afferents is accompanied by irritation or pain (Acosta et al., J Physiol 534: 511-525, 2001; Acosta et al., Invest Ophthalmol Vis Sci 42: 2063-2067, 2001; Acosta et al., Invest Ophthalmol Vis Sci 45: 2333-2336, 2004). In addition to polymodal and mechanoreceptive afferents, the cornea is innervated by neurons that are sensitive to innocuous cooling (Belmonte and Giraldez J Physiol 321: 355-368, 1981; Hirata and Meng Invest Ophthalmol Vis Sci 51: 3969-3976, 2010). These corneal cool cells are also activated by menthol, an agonist to the transient receptor potential melastatin 8 (TRPM8) channel, and by hyperosmotic stimuli (Acosta et al. 2001; Hirata and Meng 2010). Corneal cool cells are involved in a reflex that promotes tear production in response to drying of the ocular surface (Parra et al., Nat Med 16: 1396-1399, 2010).
Dry eye disease is a relatively common condition characterized by inadequate tear film protection of the cornea. Dry eye symptoms have traditionally been managed with eyelid hygiene, topical antibiotics (erythromycin or bacitracin ointments), oral tetracyclines (tetracycline, doxycycline, or minocycline), anti-inflammatory compounds (cyclosporine) and corticosteroids which are often time consuming, frustrating, and frequently ineffective or variably effective treatments. Tens of millions of people are affected worldwide by dry eye, and nearly five million Americans 50 years of age and older are estimated to have dry eye. Of these, more than three million are women and more than one and a half million are men. Elderly people frequently experience dryness of the eyes, but dry eye can occur at any age. Dry eye is a potentially disabling disease adversely impacting the vision-related quality of life. Current therapeutic options are limited and costly. Despite the high incidence of dry eye disease, it still remains a therapeutic challenge.
Accordingly, there remains a need for new therapies to treat dry eye disease.